This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. One of the greatest recent triumphs in the field of cancer therapeutics is the class of drugs known as tyrosine kinase inhibitors, which have been remarkably effective for the treatment of specific diseases. However, little is known at the molecular level about how these drugs actually cause cancerous cells to die. Recently, we have found that exposing a leukemia cell line to one of these drugs for as little as 20 minutes triggers an irreversible process of cell death, despite the observation that the activity of the protein targeted by this drug is rapidly restored after washing the drug out. We speculate that subtle irreversible changes are occurring in these cells despite only a brief exposure to the drug. Because the protein that is targeted by the drug is known to be a kinase (a protein which phosphorylates other proteins), we aim to evaluate global changes in phosphorylation following a brief treatment of this cell line with the drug. We hypothesize that the true mediators of this commitment to cell death will be identified as those with persistent changes in phosphorylation status. It is our hope that by understanding the molecular changes in this experimental system, we will be able to not only gain valuable insight into the mechanism of action of a highly effective therapy, but also to identify new molecular targets for the treatment of a variety of cancers.